Exogenous type D SRV infection is the cause of most simian acquired immunodeficiency-associated mortality in biomedical research colonies of Old World macaques. The effects of various type D SRV isolates on the immune system have not been extensively studied, but clearly there are low and high pathogenic virus strains. Envelope diversification appears to be a mechanisms whereby retroviruses that share a common receptor persist in uninfected host. These molecular changes in the virus envelope are associated with altered cell tropism and escape from immune surveillance. The proposed studies will explore the relationship between envelope glycoprotein determinants that affect cell tropism and immunopathogenesis. We have isolated SRV D2/RHE/OR and a closely related variant, V1, that differ in their replicative ability for rhesus macaque T lymphocytes. Envelope sequence analysis revealed a mutation-rich region that may represent a mutational "hot spot". The following studies are proposed to determine the biologic significance of this putative hypervariable region: i) isolate full-length infectious clones of prototypic and variant SRVs, ii) construct chimeric prototypic-variant SRVs, and iii) determine cell tropism of parental and chimeric viruses for T and B lymphocytes in vitro and their pathogenic potential in vivo. The proposed studies will investigate the differences in virus distribution in cells of the immune system and host immune responses for prototypic, variant, and env chimeric viruses. The relative stability of type D SRV may provide the opportunity to identify the precise envelope determinants that affect tropism and pathogenesis and provide a model system to study virus genotypic determinants of immunopathogenesis among retroviruses that utilize a common receptor site.